16 December 2009

There was a very interesting article published in the 05 November 2009 issue of Science magazine on the composition of bacterial colonies in humans. A human has more bacterial cells living in and on it than it does have human cells. Costello et al. (2009) (also see Supplemental Online Material which I think is free access and comprises 90 % of the article) took bacterial samples from 7-9 humans (likely the authors' themselves) over several months to assess both the composition of bacterial colonies from various sites such as the gut, forehead, and nostril, and to assess whether the composition changed with time. They found significant variation from person to person but not a lot of change over time. Hence the notion that we all have our own individual bacterial flora.

Bacteria on the surface of the various membranes that separate our innards from our environment are essentially the first line of defense against intruders. They form more or less continuous biofilms consisting of bacteria held together by a matrix of congealing substance, such as mucous. Bacteria colonies on our bodies are mostly symbiotic, although they can be parasitic at which point they become pathogens. So there are 'good' and 'bad' bacteria. What determines whether we have mostly 'good' symbiotic bacteria or not? How do we encourage the development of 'good' bacterial flora and discourage harmful flora? Good bacteria can out-compete pathogens, predigest anti-nutrients before they can penetrate the gut lining, thereby providing useful symbiotic services to us.

These are questions I do not have answers to, but I do have hypotheses.

Bacteria are prokaryotes, which means they are much much smaller and simpler than any one of our cells in our body. In fact they are about the same size as the mitochondria organelles in our cells. Mitochondria are the ATP-producing energy factories of our cells, and all they do is break apart fatty acids (called beta-oxidation) and oxidize Acetyl-CoA, the produce of beta-oxidation and glycolysis of glucose. A bacterium has to to all that and more all in a small package. As a result, bacteria often can only exist on certain nutrients: lactose, glucose, fatty-acids with a certain number of carbons, etc. These are called metabolic pathways, and they represent a specific set of chemical reactions that eventually result in the production of ATP, the energy currency of living things.

The obvious conclusion to draw here is that macronutrient ratios will likely be fairly important for determining the composition of gut flora, but it will not be a question of carbohydrate versus fat. It will be a question of 4-chain saturated fatty acids versus 18-chain monounsaturates, glucose versus fructose versus galactose, because that's the level of detail required for metabolic pathways. In addition, there is almost certain to be some synergy between various forms of bacteria when they form little symbiotic colonies, with one living off the metabolic produces of the other.

Micronutrients may also matter to gut biofilm composition. Most biochemical processes in the body require enzymes to catalyze the reaction. Enzymes are usually protein chains in which one amino acid group has had a elemental substitution that acts as an active site with chemical activity. An example is the iron site on hemoglobin that binds oxygen in your red blood cells. I would guess that bacteria can do the substitution themselves, which is to say they should be able to build their own enzymes from the elemental forms of the required minerals rather than necessarily requiring the amino group preformed. The point I am trying to make is mineral deficiencies might kill off various strains of gut bacteria.

Overall I think this line of research is very interesting and likely to provide many interesting results. This might, for example, end up being a very strong argument against the prophylactic employment of antibiotics. At a minimum, patients should be prescribed probiotic cultures after their antibiotic treatments, and, oh yeah, those probiotics should actually be, you know, alive when ingested.

A useful research project would be a large-scale longitudinal study (tens of thousands of patients over 10 - 15 years), where patients' gut bacterial colonies are sampled at regular intervals and the patients are monitored for the development of various diseases. The initial states of gut flora, if they remain consistent, may produce correlations for the relative risks of various diseases. If the composition changes, the natural question is if any new diseases presented at the same time. The US National Institute for Health has instituted a survey program to determine the genomes of gut flora, the Human Microbiome Program, which is an important first step.

I started taking a Lactobacillus and Bifidobacterium probiotic a couple of weeks ago as a trial. I did notice changes in my stool almost immediately; for the sake of brevity I will spare you the details. Bacterial cultures, like fish oil, should be stored in the refrigerator but unlike fish oil bacteria don't withstand freezing too well.

16 November 2009

Mmm... butter, one of the tastiest of all fats. It also happens to be one of the most nutritious forms of dietary fat, containing the fat soluble vitamins A and D in their animal usable forms. It is also a good source of vitamin K2, which regulates calcium metabolism; K2 has become quite rare in our modern diet with its lack of fermented foods. Unfortunately, butter does contain some milk solids, so if you are gluten intolerant you may also be intolerant of the α-casein that makes up some 80 % of cow milk proteins. It also contains a little bit of lactose, which might make someone with lactose intolerance hurl. What to do? Why remove the milk solids of course. This process is called clarification and can easily be done on the stove top. The finished produce is often called Ghee, as it was once a staple of Indian cooking.

An additional advantage to clarifying butter is that it does not brown or burn nearly as easily so cooking with it at high temperatures is safer. Traditionally ghee is often flavoured with cinnamon or cloves. Incidentally cinnamon is a folk-method for treating diabetes; it has an insulin-like effect in addition to being high in chromium.

I typically clarify two pounds of butter at a time. Since the volume of the butter will be reduced by about 1/4 (primarily water and the filtered milk solids) this yields about 750 mL of high quality cooking fat. You'll want the following ingredients and apparatus:

2 lbs. butter (cultured butter will taste better)

optional: wholes cloves and cinnamon stick

sauce pan

ladle

thermometer, digital w/ alarm

strainer

elastic band (like the type broccoli stalks come with)

terrycloth or cheesecloth

First start by melting the butter in the pan on low. As it melts to cover the bottom of the pan you can turn it up to medium and stick your thermometer into the oil. Set the alarm to 110 °C (230 °F). You don't want to use high heat here, as there's only a limited amount of water in the butter so it's mostly just a matter of time for the oil to heat up.

When water evaporates it takes away an enormous amount of heat, so the temperature of the ghee will stall a bit at or just above 100 °C (212 °F). At this point, the butter will separate into its three constituents: the milk solids, which will settle on the bottom, the golden-coloured oil itself, and a layer of foam on the top.

The foam does not contain casein, but it is unsightly and we want to get rid of it with our strainer. Just skim around the top, and then wash the strainer off with hot water. After 2-3 skims, you should have a cleaner looking product.

After cleaning off the foam you are essentially just boiling away the water content of the butter. Honestly if you know what you're doing and watch the butter carefully you don't need the thermometer. As the oil heats up, the bubbles will get smaller and smaller. When the oil stops bubbling, that means all the water has evaporated and the temperature of the oil will start to rise very quickly. When or if the milk solids at the bottom of the pan start to turn brown, remove the pan from the heat immediately. I generally wait until 125 °C (257 °F) to finish heating.

At this point it's time to transfer the clarified butter into your jar. I use terrycloth instead of cheese cloth for a few reasons. One, it is far cheaper and easier to find. It's even reusable, and it seems to do a better job of filtering the milk solids than cheesecloth. I do wash it beforehand. The elastic is wrapped around the base of the strainer to hold the filter in place.

That's it! Now just cap your jar and clean up. The hot ghee will be transparent and look a fair bit like thick urine. If any milk solids did make it through the filter process, they will settle on the bottom. As it cools to room temperature, it will become more solid and turn a pale yellow colour.

Ghee is shelf-stable although I would store it in a cupboard away from light. It can be refrigerated but it becomes very hard at colder temperatures and impossible to get out of the jar with a spoon.

If you can't afford high-quality grass-fed organic butter (I certainly can't), you may want to consider adding vitamins D3 and/or K2 if you can buy them in drop form. Add them to the finished ghee in the jar and stir.

01 November 2009

I would like to share an overview of how and what I eat, and why. Rather than list individual food items, I will discuss the approach in general terms. I won't really be rigorously supporting many of my statements since that would require an entire book or more worth of writing. I will try to keep this brief and information dense.

I structure my nutritional philosophy around the notion of the Paleolithic Principle. The principle is that the human animal has been around and eating a relatively consistent diet for a couple of million years with Homo Sapiens being around for almost 100k years. It was only really with the introduction of the neolithic age that technology brought new foodstuffs to consume such as dairy, grains, and the other modern cultivars of plants that we eat. The paleolithic principle states that we have not fully adapted to these new types of foods and hence they may be harmful to our health, on a case by case basis.

These new sources of food were introduced roughly 5000 - 7000 years ago, which is perhaps some 300 generations worth of time. Humans, being long-lived, evolve quite slowly. Humans, being highly social sentient apex predators, also don't necessarily experience the same degree of natural selection as other species. The question is then, just how well adapted are we to these neolithic food groups?

We know for a fact that food tolerances have an ethnic bias. We know that the closer one's ancestors hailed from Mesopotamia the less likely they are to be intolerant to wheat gluten. Similarly, Asians are far more likely to be lactose intolerant than Europeans. Thus, clearly, only certain segments of the human population have adjusted to each particular Neolithic foodstuff. These are established facts, and they provide a basis for the paleo principle as a reasonable hypothesis.

If one has an ethnic background that strongly identifies with a particular ethnic diet then you might be best off following it since you're probably selected for it. This doesn't always work well however, especially in the immigrant nations such as the USA and Canada, where there has been a great deal of mixing in ethnic groups. Personally, I'm a mix of Polish-Romanian jew, Italian, French, Norwegian, Scottish, Austrian, and English, with a few other nationalities thrown in for fun. If I were to follow an ethnic diet, which of the ten or so should I pick? Almost all of the neolithic food groups give me some trouble. Perhaps I'm simply lacking in intestinal fortitude.

The largest quantity of pharmaceuticals that one ingests by far is in the form of foodstuffs. Plants especially contain an enormous number chemical compounds, not all of which are broken down before they cross the gut-blood barrier. For whatever reason, the gut-blood barrier and the associated bacterial biofilm has broken down more commonly in modern man.

Of course, even foodstuffs that we have been (slowly) adapting to over 5000 - 7000 years have changed a great deal. For example, the heavy fertilization of dwarf wheat strains has resulted in higher protein yields but that protein predominantly comes in the form of increased gluten content. So when people scratch their heads about the increased incidence of celiac and other gluten related autoimmune disorders, it may just be that the wheat is changing rather than the people, n'est-ce pas? Similarly ever compared a wild strawberry to a super-fertilized all-season Californian monstrosity? We have started supplementing our diet with artificial food additives, such as mono-sodium glutamate (MSG), which only further complicates our understanding of nutrition.

Modern farming practices, cultivars of plants, and breeds of animals sacrifice micro-nutrient content for economy in the form of macro-nutrient content. In some cases, you don't even get more macronutrient, but just more water content for the check-out scale. Thus you have the paradox of a person who is obese yet simultaneously starving thanks to a diet of soda pop and it comes about due to the imbalance in the ratio of micro-nutrients to macro-nutrients in the foods we eat. This is the tyranny of the middles aisles in the supermarket.

Now, the paleolithic principle is sort of like using a sledgehammer to pound in a finishing nail (HT: Chris). It works, it works quite well actually, but it is an excessive means to the task. I don't ascribe to the fairy tale view that everyone was engaged in happy-fun-time back before the introduction of agriculture but there's little doubt that hunter-gatherers were physically far more impressive animals than the more numerous agriculturalists and pastoralists that out-competed them.

It's clear to me that industrialization and technology has had a number of negative consequences to human health which we call the "diseases of civilization." The most obvious of these are heart disease, diabetes and obesity (including metabolic syndrome), but they also include autoimmune disorders (which are far more common than is generally recognized) as well as many neurological disorders. I don't think it has to be this way, but there have been some very wrong-headed paths taken in the field of nutrition over the past fifty-odd years.

From an evolutionary perspective, the more recently a particular foodstuff was introduced, the more likely it is to cause distress. This implies that refined oils and large quantities of fructose, both of which were entirely absent in the 1800s, are two of the more obvious places to eliminate and cut-back in order to restore the good health nature intended us to have.

If I were to sum up a reasonably brief list on what to do and what not to do, this would be it:

Control appetite hormones like gherlin by eating regular, satiating meals. By satiating I mean protein, fat, and fibre. Try to avoid snacking.

Restrict fructose and alcohol consumption to reasonable levels, day-to-day. 20 g/day of both combined would be a very healthful level, 50 g/day is I think an upper bound for people with healthy livers.

Eliminate industrial, refined oils, particularly refined polyunsaturates such as soy and canola oil. Go for fresh and high quality fats, in particular clarified butter, extra-virgin coconut oil, extra-virgin olive oil, and the fats from animals fed their native diet. Unstable oils should be stored in the refrigerator or freezer to prevent them from going rancid, e.g. Omega-3 fish oil capsules. Most industrial oils are deodorized to prevent you from smelling when they go bad.

Eat more than just muscle meat from an animal. Have you eaten liver pate or roasted heart lately? Bone broth?

Fast occasionally for approximately 24-hours to give your liver a break and restore insulin sensitivity. Many religious groups noted for their good health (i.e. Seventh-day Adventists, Mormons, and the Greek-Orthodox of Crete and Corfu) regularly fast — is the the shared common trait. Fasting and starving are not the same thing, don't conflate the two.

Go on elimination dietary trials of the common food allergies: wheat (including barley and rye), cow dairy, legumes, especially soy and peanuts, tree nuts, eggs, fish, and shellfish. Test assays may be insufficient to recognize many of the idiopathic problems (i.e. autoimmunity, neurological disorders) that these types of food may induce. It took me six months wheat-free to get better.

Supplement with Vitamin D, on the order of 1000 IU/12 kg of body mass per day. Consider that the recommended doses for infants are 400 IU/day, so if you mass ten-times that of an infant, you need ten-times as much vitamin D; recommended adult doses are a joke. Also consider that you produce about 10,000 IU/ 30 minutes in full-sun. Vitamin D is not a vitamin, it is the precursor material to most of the steroid hormones in your body. When the endocrine (hormone) system has adequate signaling compounds, the whole body works better.

I do not eat much in the way of carbohydrates primarily since wheat and dairy are off-limits to me but even more so was the realization that foodstuffs that are good sources of glucose are also bereft of micro-nutrients. I.e. they are empty calories. You know how some people drink socially? I eat grains socially (with the notable exception of wheat, which I find incredibly destructive to my body). This said I don't believe glucose is inherently a problem and I do carb-load from time to time.

You may have noticed that I haven't talked about exercise at all, and that's because I think it is relatively unimportant. If you apply the 80/20 rule to how well you feel, I think perhaps 80 % of your wellness comes from diet, 15 % from adequate restful sleep, and perhaps 5 % from physical activity. Trying to lose body fat from exercise is a fool's errand and more than likely will result in over-training and the associated chronic injuries. While I personally do get a lot of physical activity, it's all for fun. My current hobby is whitewater kayaking, so any physical training I do is oriented towards improving my performance in that regime rather than building bulging biceps. I don't bother lifting weights in the gym since I find it quite dull. The fact of the matter is I got healthy through diet first and only then started exercising more.

Now, you may have noticed me talk about autoimmunity a lot and that is because I think it plays a key role in the diseases of civilization. Autoimmunity is simply the case in which the immune system, which is responsible for both healing and repealing foreign invaders, starts attacking the tissues of its host body. Autoimmunity has a genetic component, but something needs to trigger it. Examples are viral or bacterial infections, or dietary allergies. Celiac is one type of autoimmune disorder, type 1 diabetes is another.

If the diet is introducing strange, novel foreign bodies into the gut and the gut is compromised, they will penetrate into the circulatory system. The immune system sees these foreign bodies and goes berserk trying to hunt them all down and destroy them. Then, four to six hours later, you eat another meal and the cycle repeats. The solution is to remove the stimulus, i.e. fix the diet.

Any sort of food allergy or intolerance is likely to result in the immune system being depressed. The immune system only has a finite capacity for fighting infection, and if you're making it waste its time chasing gluten peptides or whatever, it is not going to be so strong at fighting off the latest pathogen. Similarly if you are not providing the immune system with enough micro-nutrients to operate at full capacity you will not only get sick more often, but you will also heal more slowly.

If I could sum up my nutritional philosophy in one sentence it would be:

Don't eat things that cause your immune system to run around like it has a hole in its head.

14 October 2009

Until now, however, redox flow batteries have had the disadvantage of storing significantly less energy than lithium-ion batteries. The vehicles would only be able to cover about a quarter of the normal distance – around 25 kilometers – which means the driver would have to recharge the batteries four times as often. “We can now increase the mileage four or fivefold, to approximately that of lithium-ion batteries,” Noack enthuses.

Mmm... vague, yes? As anyone who has been following the alternative energy scene for any length of time knows, the bigger the claim and the fewer facts behind it, the more likely it is to be BS. As always, it pays to be skeptical rather than credulous.

If you aren't familiar with the technology of flow batteries, I suggest you buck up to Wikipedia and take a read. The strong point of flow batteries has always been that the power and energy storage characteristics are decoupled: the power is a function of the size of exchange membrane, while the energy storage is determined by the volume of the storage tanks. In this fashion, they are a lot like fuel cells except that they are reversible. However, the energy density (as a function of weight or volume) has never been terribly impressive, lying around that of lead acid batteries.

The engineer who is quoted in the story, Noack, appears to be involved with the design of the exchange membrane and I can't see the mechanical bits resulting in a 4 - 5 fold improvement in energy density. I found a paper he wrote here comparing the various known chemistries applied to a new membrane stack design. There must have been some new chemistry developed, either that or there's smoke and no fire here. The article does mention collaboration with the University of Applied Sciences, Ostphalia [sic], but I can't find anything pertinent on the university's web site.

The previous king of the various redox flow battery chemistries is the Vanadium redox battery. It can, in general, obtain a 75 % round-trip efficiency which is fairly decent, being roughly in-between Li-ion batteries and Nickel-metal hydride batteries. The Achilles heel has always been the chicken and egg problem of the cost of Vanadium. Vanadium is not a particularly rare element, but it isn't mined in large quantities due to lack of demand and hence it is quite expensive. A single utility scale redox battery would consume a significant portion of the world's annual Vanadium production. Thus the conundrum, if no one can afford to buy a Vanadium redox battery, you'll never generate enough demand for Vanadium to open up new mines and drive the price down. The best hope, I always thought, was for one of the Vanadium-contaminated oil deposits of the world to be developed and glut the world Vanadium market.

28 August 2009

Heart disease, or more specifically atherosclerosis, is a chronic disease whereby cardiac arteries become partially occluded by the growth of plaques. Narrowed arteries are more likely to trap dislodged blood clots, resulting in blood supply being cut off to a portion of the heart, resulting in oxygen depletion of the cardiac muscle tissue and eventually myocardial infarction or heart attack.

Contrary to common wisdom, dietary fat does not deposit on the arterial wall and "clog your arteries;" plaques grow inside the arterial cell wall and consist of a mix of the smooth muscle cells that naturally line the interior lining of the artery and immune-system cells such as macrophages and lymphocytes. Macrophages, or white blood cells, are the large, amoeba-like cells that form the last line of defense for the immune system. This mix of cells are called foam cells. Foam cells tend become bloated by absorbing large amounts of cholesterol from the blood stream and they form a cyst or lesion which compresses the arterial wall, reducing the effective diameter.

By way of background, there are three times of muscle in the body: cardiac, skeletal (meat muscle, like your bicep), and smooth muscle (such as your scalp or vital organs). Smooth muscle is quite a bit different from the other types in that its cytoskeleton has no deterministic, regular structure. Rather, it just consists of a chaotic jumble of actin filaments. Unlike the other two types, smooth muscle is not normally controlled by the electronic action potentials of the nervous system; rather, it is controlled by the much slower chemical hormonal system.

With time, atherosclerotic lesions may harden by absorbing calcium from the blood which makes the artery stiffer and tends to result in high blood pressure. This is not unlike how bone tissue is formed by the mineralization of connective tissue, which in turn suggests some sort of hormone dysfunction is in play. Hardened arteries are considered more hazardous than pliable yet still narrow arteries. The likely reason for this is that a narrowed yet pliable artery can distend under pressure to allow a blood clot through, while a calcified artery cannot.

Thus we have three criteria for heart attacks (with some simplification):

The wall of the cardiac artery has to be sufficiently narrowed so that,

The arterial wall is too stiff to allow the build-up of pressure caused by the obstruction to allow the clot through, resulting in down-stream oxygen deficiency and eventually cell death.

To reduce heart attacks, you can attack any of these three processes. Take the Masai tribesmen of Tanzania: they have a great deal of atherosclerosis thanks to their milk-based diet, but they don't necessarily suffer heart attacks, likely due to their adequate intake of vitamin K2.

I want to talk about the first requisite, atherosclerosis. The question is of course, what causes immune system bodies to form colonies inside the lining of one's arteries? There are two basic possibilities: auto-immune disorder, where the immune system recognizes legitimate tissue as foreign, or actual foreign bodies, such as chronic bacterial or viral infection of the blood vessel. Or both.

Enter Chlamydia pneumoniae, bacterium

The idea that atherosclerosis might be caused by chronic infection of the lining of blood vessels is not a new one. In 1999, the American Heart Journal devoted a supplementary issue to the topic. It is, essentially, an alternative theory for heart disease as compared to the diet-heart hypothesis, whereby diet modifies serum cholesterol levels which in turn causes heart disease by some unknown mechanism. As it contraindicates the standard lipid model, it is considered controversial. The first potential pathogen candidate was cytomegalovirus (aka herpes) but it turned out to be a bust.

Further research suggested a better candidate. Chlamydia pneumoniae (aka Chlamyophila pneunomiae) is the bacterium most commonly associated with heart disease in the literature. As the name suggests, it is one of the sources of pneumonia and other respiratory infections. It has also been associated with Alzheimer's and asthma. It is a relatively recently discovered pathogen (in that the diet-heart hypothesis was formulated before anyone knew it existed), and its responsibility for respiratory infection was only discovered in 1986 (Grayson etl al., 1986). The association with heart disease was made very quickly (Saikku et al., 1988), since the hunt for a potential atherosclerotic pathogen had been underway since the early 1980s.

Exposure to Chlamydia pneumoniae is extremely common, and respiratory infections occur repeatedly among most people. Strong associations exist between C. pneumoniae infection and atherosclerosis as demonstrated by: (i) sero-epidemiological studies showing that patients with cardiovascular disease have higher titres of anti-C. pneumoniae antibodies compared with control patients; (ii) detection of the organism within atherosclerotic lesions, but not in adjacent normal tissue by immunohistochemistry, polymerase chain reaction and electron microscopy and by culturing the organism from lesions; and (iii) showing that C. pneumoniae can either initiate lesion development or cause exacerbation of lesions in rabbit and mouse animal models respectively.

This list is not exhaustive, and it does not note probably the most important point: C. pneumoniae can create foam cells in vitro (i.e. in a Petri dish). C. pneunomiae has been shown to infect the constituent cells in foam colonies (i.e. macrophages and smooth muscle) (Fryer et al., 1997), inhibit the mechanism whereby cholesterol (LDL) is relinquished (Kalayoglu, 1999), and oxidize low-density lipoprotein (LDL) via releasing heat shock proteins (Kol et al., 1998). More on this later.

The physical presence of C. pneunomiae in atherosclerotic lesions has, as previously mentioned, been detected by a wide variety of methods. It's also highly prevalent. Of many studies that have found C. pneumoniae in foam colonies, (Muhlestein et al., 1996) is probably the most solid. From a population of 90 patients, they found evidence of C. Pneumoniae in 79 % of atherosclerotic plaques, but only 1 of 24 control biopsies.

A basic question then is how does one particular type of bacteria manage to not only evade the immune system, but distort its response in order to cause great harm to the host? (Belland et al., 2003) explore the mechanism,

Chlamydial growth is biphasic, consisting of two alternating functional and morphological forms (Fig. 1). The elementary body (EB) is the metabolically inert, infectious form of the organism that is capable of transient extracellular survival. EBs bind to as yet undefined host cell receptors, are internalized via a pathogen-specified process and are detectable within a membrane-bound vesicle immediately after entry. This vesicle is capable of interacting with post-Golgi secretory vesicles in ways that allow for the incorporation of host phospholipids [RM: phospholipids are cell membranes, i.e. camouflage] (Hackstadt et al., 1996; 1997). Chlamydiae also block intracellular host cell responses, such as fusion of the pathogen-containing endosome with lysosomes, and thus avoid host cell factors that would be detrimental to intracellular survival. Soon after entry, chlamydiae differentiate from infectious EB to the intracellular replicative form of the organism, referred to as the reticulate body or RB. This differentiation, which is dramatic in terms of altered chlamydial morphology, must reflect an orchestrated sequence of differential gene expression. Transformation of EB to RB results in loss of the disulphide cross-linking of the outer membrane complex, decondensation of the genome and initiation of DNA, RNA and protein synthesis. RB multiplication results in the formation of an intracellular microcolony (termed the inclusion) of chlamydiae.

Ok so that's a wordy quote, but to sum it up in one word it is mimicry. A big area of research in bio-nanotechnology is the development of phospholipid coatings on implanted medical devices to prevent the immune system from recognizing them as foreign and attacking them. This technique is known as, "stealth technology." Here we have an example of an organism that has evolved this technique. <acerbic>But don't you dare eat any eggs, they have cholesterol in them</acerbic>.

It's not clear if C. pneumoniae causes all atherosclerosis but I do believe it causes a majority of such. Another potential source of plaque-forming bacteria is Helicobacter pylori, which among other things, is thought to be responsible for ulcers. Unlike C. pneumoniae, which enters through the lungs, H. pylori typically lives in the gut. A study by Mayr et al. (2000) found an association between H. pylori antibodies and cardiovascular disease, but only in the low status (i.e. poor) individuals in their population. This study was conducted in Austria, so one wonders what might poor Austrians be eating that would cause them to suffer H. pylori infections?

The same paper also found odds ratios for: IgA type antibodies to the C. pneumoniae bacteria, elevated C-reactive protein levels in the blood, and (clinical) chronic respiratory infection. Now, odds ratio is a funny, non-intuitive statistic, but we can directly compare it to odds ratios found in other studies.

As you can see, three out of three is quite a strong association, far stronger than the cholesterol testing that is the most common method of screening for heart disease risk in medicine today. It is actually getting close to that of smoking and lung cancer, which is the gold-standard for causation. If you break it down individually, the strongest of the three criteria is chronic respiratory infection (OR of 3.8), followed by C-reactive protein (OR of 2.4). Since C. Pneumoniae antibodies has the poorest odds-ratio, while the chronic conditions are much higher, we can probably surmise that being infected once isn't going to cause atherosclerosis, in the same sense that over-drinking once is not going to cause fatty liver disease. Heart disease is a chronic condition, caused by chronically applied vectors (i.e. diet and environment). For the same reason, antibiotics were found to be ineffective in treating atherosclerosis: they are effective for acute infection, but in the long run they cause as many problems as they solve, since many of the bacteria in our bodies are beneficial and help out-compete teh nasties [sic].

Heat Shock Proteins

Another issue, that I eluded to above, is what exactly is causing inflammation in this case? Medicine has identified oxidized-LDL as a major danger factor, but is this a cause or just a symptom?

One potential candidate is a class of proteins that are produced by cells under stress, collectively known as heat shock proteins. The name is not well chosen, heat shock proteins should be termed temperature stress proteins. They are produced by cells that are under elevated temperatures (or many other forms of environmental stress) and they protect the other functional machinery of the cell from future elevated temperatures. They are considered to be a part of the general inflammation response of the body, although they tend to operate on a small, single-cell (i.e. autocrine) scale.

Foam cell colonies produce one particular type of heat shock protein, HSP60, in large amounts.This particular heat shock protein is usually associated with mitochondria, the energy factories of cells, but it's also known to interfere with apoptosis, or programmed cell death. Apoptosis is the way in which the body normally disposes of broken or old cells. Elevated levels of HSP60 prevent apoptosis from occurring (Gupta and Knowlton, 2005).

One study on 1003 Chinese men found an odds ratio of 2.3 for atherosclerosis by simply being in the top half of the population for HSP60 levels in the blood (Zhang et al., 2008, full-text link on Pubmed is broken and is available here). Those in the top quartile for HSP60 levels had an odds ratio of 4.87, which higher yet than the range usually seen for c-reactive protein, which is the standard marker for inflammation.

The high odds ratio with c-reactive protein has been seen as one of the supporting features for the slowly evolving, mainstream view that inflammation and not blood lipids are responsible for heart disease. But is inflammation the cause or symptom again, and what causes localized inflammation of the blood cell wall anyway? The fact that arterial foam cells produce heat shock proteins and a bevy of other inflammatory markers in quantity suggests that atherosclerosis causes inflammation, rather than the other way around. Indeed, studies have claimed that the chlamydial heat shock protein 60 (cHsp60) oxidizes LDL particles in a test tube (Kalayoglu et al., 1999). This is big deal, since the actual mechanism whereby LDL oxidizes isn't known. For example, see Steinberg, 1997:

First, patientsand animals totally lacking the LDL receptor nevertheless accumulatecholesterol in foam cells much the same way as do patients andanimals with normal LDL receptors; second, the two cell typesin lesions that give rise to cholesterol-laden foam cells (themonocyte/ macrophage and the smooth muscle cell) do not accumulatecholesterol in vitro even in the presence of very high concentrationsof native LDL (3,4). This paradox could be resolved ifcirculating LDL underwent some form of modification and if themodified form, rather than native LDL itself, then served as theligand for delivery of cholesterol to developing foam cells.

There are no paradoxes in medicine, just an inadequate understanding of nature. That, and a heaping load of bias. If it is the heat-shock proteins that are causing much of the trouble, then we have some idea as to why foam cells are sustained by the body. The heat shock proteins produced by these bacteria closely mimic the same heat shock protein produced by the arterial wall (Hsp60). Heat shock proteins are one of the basic lego blocks of living cells, and there's not a great deal of variation between those HSPs produced by highly evolved human cells compared to say, yeast. The fact that HSP60 inhibits programmed cell death is another fascinating thread to pull on. Another possibility that occurs to me is that real bacterial infection may be transformed over a long time into an auto-immune disorder, even if the original bacteria have died off. More research is needed to assess just what the half-life of C. pneumoniae is in foam cell colonies.

Known correlations with heart disease

So how are these bacteria getting through the mucous tissues and into the blood stream? The correlation between smoking and heart disease is explained nicely by this hypothesis. Smoking compromises the lungs, leading to C. pneumonia or some other form of infection, which in turn results in atherosclerosis.

One might expect then that other chronic conditions that break down the walls of the mucous membrane/exterior environment barrier could also lead to atherosclerosis: dietary components that cause leaky gut, periodontal disease, and possibly fungal infections. Alternatively, substances that suppress immune system function could be associated with cardiovascular disease.

Other chronic diseases that results in a breakdown of the bloodstream-mucus-environment barrier should also show increased rates of heart disease. The two most obvious choices to me are celiac disease (where wheat gluten destroys the lining of the intestines) and periodontal disease (of the gums in the mouth). For celiac disease, there doesn't seem to have been any research on the topic. Of course, it would be ethically impossible in a clinical setting to find undiagnosed celiac patients and follow them to assess heart disease. Once celiacs are diagnosed, their treatment is straight-forward (i.e. don't eat wheat or casein). However, perio is more difficult to resolve and the results on periodontal disease seem to be consistent, with perio causing a small (relative risk 1.24-1.34) yet consistent and significant increase in heart disease average over many studies (Cronin, 2009).

Similarly, substances or deficiency of certain materials in the diet that suppress or deform the immune system response could have an impact on heart disease. The most obvious would be insufficient vitamin D intake.

Conclusion

When it comes to the diseases of Western civilization/diet, we always must ask the question, what is the mechanism? A top-down approach is simply insufficient because separating correlation and causation in living organisms is so difficult and one is consistently tempted to simplify the details rather than break them down into first principles. Hence the enormous failure of pursuing cholesterol as a cause of heart disease, instead of recognizing it as a symptom. The false path of the cholesterol hypothesis has to rank of one of the greatest scientific blunders of all time and is indirectly responsible for the premature deaths of millions.

On the other hand, the chronic infection theory of heart disease is internally consistent with the data that are available to us. We know that C. pneumoniae is a common form of respiratory infection, and that once in the bloodstream it can infect smooth muscle and macrophage cells both in vivo and in vitro. We know that C. pneumoniae can disrupt the cholesterol metabolism of foam cell colonies in vitro. The chameleon nature of C. pneumoniae illustrates how foam colonies can be be persistent in the face of the immune system and morph an acute infection into a chronic condition. I just don't see any gaping holes in the theory. We still need to explain why C. pneumoniae (and other bacteria like H. pylori) affects some individuals and not others, but the how is reasonably explained and justified.

26 August 2009

Bill Gates recently purchased the rights to a series of lectures by renowned physicist and teacher Richard Feynman. Feynman was a nobel winner for and essentially the father of the field of quantum electrodynamics, and also did a lot of work on superfluidity of liquid helium. The breadth of his contributions has to mark him as one of the top physicists of all time, possibly top-five, certainly top-ten.

Feynman proves the adage that it is not science that is staid and boring, but rather scientists are staid and boring. Anyone who has written journal publications will know what I'm talking about here.

You will need to download and install (Firefox users: manual installation) a Microsoft plug-in to view them but they are really a great resource. In short, they are a perfect way for someone who has only a cursory understanding of science and wants to know more, yet doesn't know where to start. For experts, they are still useful to get your mind out of the minor details that dominate scientific discourse today and thinking about the big picture once again.

My favourite lecture by far is #6 on the dual wave-particle nature of fundamental particles like photons and electrons. This lecture is very close to one of my thesis topics, on the double slit experiment. Interestingly, around thirty minutes in Feynman becomes partially incorrect as he talks about the coherent and incoherent modes as in reality, there is only partial coherence.

Har har har... (you have to be a physicist).

For very small angle scattering, i.e. ΔE/Eo is very small, the interference is less but still present. To put numbers on these, we're talking about ΔE=1-20 eV energy loss compared to Eo=300,000 eV in the denominator, or angles less than 0.004 °.

08 July 2009

Key et al. reported in the British Journal of Cancer a large observational study that compared cancer incidence between groups based on diet. This article claims to be free access to the public. The corporate media love to report on research like this because they find it simple to tease good headlines out of them. Unfortunately, the closer you look at observational studies, the less sure of anything you end up being.

The study split 61566 Britons into three groups, 'meat-eating' (N = 32403), 'fish-eating vegetarians' (N = 8562), and 'vegetarian' (N=20601). Unfortunately, the study did not split up lacto-ovo vegetarians from vegans, as that may have been interesting due to the removal of another food group in the form of dairy.

The 'meat eating' group could be better described as the 'standard British diet' group. There are substantial differences in the approach to food between vegetarians and the stereotypical general population. This is particularly evident in the degree of industrial, processed food consumed although when I go to organic food markets I still see plenty of crap in the middle aisles.

There were, of course, differences between the three groups that were not dietary:

The mean age at recruitment was lower in the fish eaters and vegetarians than in the meat eaters. Smoking rates were low overall, with only 14.4% of meat eaters, 11.2% of fish eaters and 11.4% of vegetarians reporting that they were smokers at the time of recruitment. The median BMI was 1.5 kg m-2 lower in vegetarians than in meat eaters, and the median alcohol consumption was 1.0 g per day lower in vegetarians than in meat eaters. Fish eaters had similar mean BMI to the vegetarians and had similar alcohol consumption to the meat eaters. The proportions of men and women who reported a relatively high level of physical activity were higher among fish eaters and vegetarians than among meat eaters. The proportion of women who were nulliparous at recruitment was higher among fish eaters and vegetarians than among meat eaters, and the proportion of women who had ever used oral contraceptives was lower among fish eaters and vegetarians than among meat eaters.

The authors claim to have corrected for these factors in their results for cancer risk factors, and that an uncorrected analysis had similar results to the corrected one (i.e. that the differences did not impact the results).

The results were statistically significant only for stomach, lymphatic, and cervical cancers, and the overall results were also significant. The uptick in cervical cancer is interesting, but not particularly important given how easily it can be avoided through vaccination. What's interesting is that the fish-eating vegetarians appear to have lower risk factors than the pure vegetarians.

It's a little hard to make the claim that meat per-say is the causative factor when you take vegetarians and feed them fish and their cancer incidence drops. In the discussion, the authors' implication focuses on nitrates and other work has shown that heterocyclic amines produced by charing/burning food (not just meat) can be hazardous. Alternatively it could be something like deep frying food in vegetable oil, since its polyunsaturated content is so easily oxidized in such an environment. Could vegetarians be buying more organic food and ingesting lower levels of pesticides? Etc. To paraphrase Simon Pegg, identifying the causative factor is like trying to hit the bull-eye on a dart-board that is mounted on a F1 car, while blind-folded, and riding a horse.

This is the drawback of observational studies: you can't make any definitive conclusions from it. At best, it can act as a guide, but it's sort of like hiking in the mountains: do you follow that old blaze when the trail forks or do you try and orient yourself? The drops in cancer rates (-18 % for fish-eaters, -12 % for vegetarians) are no smoking gun. The drop in stomach cancer is impressive. By way of comparison, the rate of lung cancer in non-smokers is roughly 3 % (i.e. RR = 0.03) compared to heavy smokers.

29 June 2009

Via Karen Howlett at The Globe and Mail, we learn that Ontario has suspended its plans to build some new nuclear power plants. The leading bid was from AECL. There have been rumblings that Atomic Energy Canada Ltd., which is a crown corporation, may be privatized by the federal government. This sort of leaking about the corporation's future probably isn't helping them land any sales. I suspect part of these funds will (have to) be restored to refurbish the existing reactors since they are going to need it to continue operating in the future. Ontario is about 50 % nuke powered; the only other nuclear plant in Canada is located in New Brunswick.

My long-standing belief is that civilization will need to build another generation of nuclear power plants to supply base-load electrical power. I've also long felt that nuclear power is more expensive, notwithstanding subsidies, than renewable sources like solar or wind will become. Initially the renewables will have to be backed by hydro where available, and natural gas everywhere else. This will eventually result in a big arbitrage opportunity for anyone who can buy cheap wind or solar power and resell it in the future, i.e. electricity storage, and make money on the margin. However, very few large thermal power plants are getting built anymore in North America or Europe, whether they be nuclear or coal powered. The experience of nations like Finland with new nuclear is not comforting.

Not replacing base-load power on schedule will accelerate the take-over of solar, wind, and natural gas but probably also result in some expensive power bills as supply and demand breaks into this natural monopoly. Using natural gas for base-load isn't the wisest use for what should be our future long-distance transport fuel, IMO.

14 May 2009

From the journal Nature, Reineke et al. (2009) report that they have successfully developed an organic, 'white'-light LED with superior efficiency to that of fluorescent tubes. They achieved efficiencies around 90 lumens/Watt, compared to fluroscent tubes at 70 lumens/Watt. In fact, if one is willing to accept less intense lighting, they were pushing 120 lumens/Watt.

Organic LEDs are more efficient when made in thinner layers, but this limits the total amount of light they can produce per unit area. So while you could technically paper the entire ceiling with them, as a manufacturer you wouldn't want to because the substrate costs money and so does shipping.

This report is really fascinating in terms of all the optical design elements they are incorporating to prevent wastage of electrons and photons. Or, at least, it is to me. Basically in order to get a material to emit light you have to have a bunch of energetic electrons. You have them decay/lose energy. One possible way to lose energy is in the form of a photon (i.e. light), but you could also shed energy as heat or just spread it out to other electrons (particularly if there are defects in the material). Or you could successfully emit the photon but it will just get trapped and absorbed by the LED before it gets into the air. For organic LEDs, photons being reabsorbed is the biggest problem.

The question-mark with organic LEDs remains lifetime, particularly for the blue wavelength versions. The ones discussed in this article only last a couple of hours. This was still the case when I first learned about them five years ago. Basically, they don't react well to oxygen.

Organic LEDs are not necessarily any better than conventional, semiconductor LEDs. They are being pursued because they are potentially very cheap and have the novelty of flexibility.

Night LightingThe strategy behind efficiency in lighting is not simply in producing the most photons per Watt of applied power, but matching the emission spectrum to that of the human eye. The unit for this is the lumen, which is the perceived brightness.

Figure 1: Sensitivity of the human eye as a function of wavelength.

The objectives for day-vision, known as phototopic, and night-vision, known as scotopic, are not quite the same. Night-vision is actually more efficient, and it peaks at a wavelength of 507 nm, which is squarely in the green part of the colour spectrum. For reference, 450 nm is the centre of the blue spectrum and 630 nm would be red.

Of interest here is the use of yellow Sodium-vapour street lamps. Low-pressure sodium lamps are highly efficient in turning electricity into light, on the order of 50-80 %. However, the human eye is not very good at detecting the yellow light (589 nm) when using the rods in the eye for night-vision. As can be seen from Figure 1, night-vision is actually piss-poor at using yellow light so when driving or walking under street-lamps, you are actually using your day vision.

Table 1: Eye efficiency as a function of wavelength.

Wavelength

(nm)

Photopic Efficiency

(lum/W)

Scotopic Efficiency

(lum/W)

470 (blue)

62

1150

507 (green)

303

1700

555 (green)

683

683

589 (yellow)

517

111

Compared to yellow sodium street lamps, a green LED could be potentially 3-times less efficient and still beat it in lumens per Watt. Of course, this isn't sufficient for driving. Depth perception requires phototopic vision, since the cones are concentrated at the centre of vision whereas night-vision is predominately peripheral. For walking paths and other applications, green LED lighting could potentially beat the pants off of sodium lamps. The ideal case would probably be a 507 nm LED with a phosphor that emits light at a longer, redder wavelength. Then both scotopic and photopic vision could be covered. Or you could just build an array that emits two wavelengths of light. In this case, the need for a blue wavelength is not quite so necessary.

07 May 2009

So I purchased a shiny (err.. matte black) new pair of Vibram Five-finger KSOs (Keep Stuff Out) last Wednesday. I tried on the Sprint as well, which pinched my right Achilles tendon.

Note that if your feet lie in the overlap region of men's and women's shoes you can fit the shoes in 1/4" rather than 1/2" intervals, with the women's being effectively 1.5 sizes smaller than a men's. I think that fit-wise, you should gage it by pulling back on the grab-loop on the back tense. Aim for 1/2" seperation between your heel and that of the slipper.

Compared to the Sprint, the KSO has a mesh upper which is supposed to keep debris from getting in and underneath the feet. The only debris I got in mine was stuff that was already stuck to my foot when I put them on. The suspension of the KSO is sort of a pulley system that attaches at the heel, comes forward and turn to pass over the top of the foot, where it attaches with velcro. The KSO (and Flow) appears to be built on a slightly wider rand than the Sprint or Classics.

The soles are remarkably sticky. There is a waffle pattern cut into the ball and heel that probably increases the friction, particularly on pavement or other flat surfaces. Running in them is not quite the same as barefoot but the degree of protection is very good. You feel everything you're running on, and sometimes things hurt a bit but only for a second and there's no lasting pain. Like barefoot, you have to watch where you place your feet, but you have considerably more insurance whenever you make a mistake, so you can run briskly. Running on a gravel track wasn't possible for me, but trails and grass were both very enjoyable experiences. I think the most dangerous thing to avoid running on would be thorns, which could conceivably slip through the toe pads and into the side of your toes.

These things appear to be very popular, and I can immediately see why. I bought my slippers on Wednesday, the saleswoman said that they got their shipment in on Monday and had already sold 1/3rd of their stock. They are sort of on the level of things like Gore-tex, Marmot's DriClime base layers, or kernmantle rope in terms of game-changing the technology and utility of outdoor gear.

Initially there was some shelf in the big-toe of my right slipper that was irritating the nail. However, with time to work in the slipper (and some work with a nail clipper) I don't notice this anymore. Pro-tip: cut your toe nails before you go to fit these. I've found the best way to set the toes is to sit with your feet flat on the floor and then raise your heels while planting your toes.

The shoes are a little sweaty, although I think this may be a feature rather than a bug: when wet the Five-fingers suction onto your foot better.

With regards to the other models, the Classic, at least to my eyes, looked to be the ultimate camp shoe for backpacking and mountaineering. Want to get your feet out of those plastic boats? Do a technical scramble? Ford a stream? The Classic model is only slightly lighter than the Sprint or KSO, however. All Five-finger models are considerably lighter than my Chaco sandles, for example, and very compact. I also think the Flow model would make a good watershoe for kayaking.

05 May 2009

I've been digging around, looking for something to interesting to write about on an energy topic without a lot of luck. Unfortunately I think alternative energy development will slow faster than the rest of the economy. If anyone has any suggestions, please voice them.

An article in the New Yorker about how overgrown the finance industry as become, and why it should shrink to better fit the size of the rest of the economy. It's nice to see this meme appear in more 'respectable' corners of the world.

An short update on the status of research into the health status of paleolithic humans. Not only have humans shrunk physically since the introduction of grains to the diet some 10,000 years ago, Americans are now also shorter than in the 1950s. What the article doesn't mention is that brain volume is now much smaller than it was in the paleolithic-era too. The cynic in me wonders if brain volume has also shrunk since the 1950s.

Are nitrates/nitrites in meat hazardous (as opposed to nitrates/nitrites in vegetables)? David Colquhoun takes a look at the science and finds it wanting. In particular, check out the dose response curves. Any actual correlation is probably due to healthy patient bias. People who are concerned about their health don't eat bacon because they think its unhealthy, not because it necessarily is. Personally, I think that the quality of processed meats varies wildly from vendor to vendor. I buy bacon from Hutterites; it doesn't have an ingredient label.

The site Beyond Vegetarianism seems to exist primarily to beat up on all fruit diets. Now there's a hard target! Nonetheless, they have some excellent articles on the likely dietary habits of paleolithic man. The article I linked goes through an extended discussion of what humans probably evolved to eat, given what we know about the anatomy of modern humans and our ancestors.

03 May 2009

I went sprinting barefoot for the first time ever today. I'm sure I've run fast as a kid on the beach, but I've never done so on a field, to my recollection. It was an impressively... natural movement. There was no pain at all in my feet, although afterward I noticed I abraded some of my calluses a bit. I did step on a clear plastic bottle cap at one point (that went into the garbage) but it didn't really hurt since I just skipped with the opposite foot.

I think I was just as fast as with shoes and I had far better control at top-speed. Normally when I reach top-speed I am wind-milling my feet as fast as possible and I feel distinctly like I am not in control until I stop running and free-wheel down to a stop. I tried to articulate my feet; I'm not sure how successful I was but like I said earlier, the movement was very natural. In retrospect, it seems obvious that bare foot running should feel extremely comfortable, as long as you don't puncture your foot. Of course, one of the advantages of sprints is you can easily scout your route for anything you really don't want to step on.

I've had flat feet for a long time, and used orthopedics in my shoes to correct my gait to avoid shin splints and other muscle and knee problems from running and walking. I'm very tempted to try and toughen up my feet enough that I can try some moderate distance running, say a couple of kilometers, barefoot and see if I develop shin splints.

I've been looking around for Vibram Five Fingers awhile now but no one local in Edmonton seems to carry them. One of my friends said she had spotted them at Mountain Equipment Co-op, but alas, they were not there today when I checked. They are present on the website, but they don't seem like the type of shoes one orders via mail order without fitting. C'est la vie.

17 April 2009

One of my hobby horses is the idea that you have to go through the glycogen stores in your liver before your body switches into fat burning mode and that this is one of the reasons cardio-style exercise is so ineffective for fat loss on a conventional low-fat diet. The opposite state, where the liver is completely full of glycogen, is also an interesting case. In this situation the liver starts manufacturing fatty acids from glucose. This is called de novo lipogenesis in the biology vocabulary. If you break this down from Latin to English, it is "generation of new fat."

There are three main stores of fat in the body: subcutaneous (under the skin), interstitial (in-between muscle fibres), and visceral (in and around the vital organs in the belly). Of the three types, visceral fat is dangerous to health while the others are relatively benign (Porter et al., 2009).

Visceral fat, typically measured by waist-to-hip circumference ratio, or more advanced imaging techniques, is a much better predictor of future diabetes or heart disease risk than the body mass index (Westphal, 2008). For example, diabetics who are relatively thin (i.e. have a low BMI) very often have what's called central obesity (Ruderman et al., 1998) or more colloquially, are "skinny fat." Fat tissue, as it happens is efficient at producing a wide variety of hormones such as adiponectin, leptin (e.g. Angulo et al., 2004), and resistin. For want of a better explanation, packing a lot of hormone-producing fat around the vital organs is bad juju.

I pose a couple of questions for the reader to ponder:

Why is visceral (belly) fat so contrary to good health? and,

What is it in our modern diet that is driving such an excess of visceral fat?

A distinct condition whereby fat deposits around the liver cause it to dysfunction is non-alcoholic fatty liver disease (see the New England Journal of Medicine review by Angulo (2002). As the name suggests, it is characterized by the appearance of fatty deposits in the liver tissue itself. Think fois gras. In addition to the formation of fat deposits, some of the more advanced forms of chronic liver disease feature the formation of fibrosis, which is the formation of scar tissue in the liver in response to repeated, chronic injury.

Funnily enough, this condition is tightly correlated with metabolic syndrome which is in turn associated with diabetes and many other debilitating conditions. Loria et al., 2005 (free) state that:

Given that metabolic syndrome and non-alcoholic fatty liver disease affect the same insulin-resistant patients, not unexpectedly, there are amazing similarities between metabolic syndrome and non-alcoholic fatty liver disease in terms of prevalence, pathogenesis, clinical features and outcome.

Loria does state that fatty liver disease does not cause metabolic syndrome, or vice versa. Since metabolic syndrome is a catch-all description of many symptoms, I think it would be fair to describe fatty liver disease as one potential component of metabolic syndrome.

The problem with fatty liver disease really appears to be the combination of insulin resistance (from ingesting too much glucose) and high circulating triglyceride levels. From the review by Petta et al., 2009, "In fact IR [RM: insulin resistance] is the key factor in the promotion of liver fat accumulation not only by inducing an increase of liver FFA [RM: free-fatty acid] influx, but also, via hyperinsulinemia, by stimulating the activity of enzymes implicated in de novo hepatic lipogenesis."

Incidentally non-alcoholic fatty liver disease was almost certainly what Morgan Spurlock was doing to himself with his soda-laden diet in the movie Super Size Me. I noticed when watching that movie that some of his doctors (2 of 3, IIRC) didn't know that the condition existed. Non-alcoholic fatty liver disease reached incidence levels of 20-25 % in an Italian population study (Bedogni et al., 2005).

Ok, so abdominal/visceral fat causes some combination of metabolic syndrome and/or fatty liver disease. So what causes people to preferentially deposit fat around their mid-section rather than elsewhere? In researching non-alcoholic fatty liver disease, I came across the following paragraph by Postic and Girard (2008, free access), which I think is instructive:

Insulin is essential for the maintenance of carbohydrate and lipid homeostasis. Insulin is secreted by pancreatic β cells in response to increased circulating levels of glucose after a meal. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes [RM: liver cells], which convert it into glycogen. However, when the liver is saturated with glycogen (roughly 5% of liver mass), any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which will be esterified into TG [RM: triglycerides] to be exported to adipose tissue as very low-density lipoproteins (VLDLs). Insulin inhibits lipolysis [RM: fat burning] in adipose tissue by inhibiting hormone-sensitive lipase (HSL), the enzyme regulating FFA [free-fatty acid] release from adipose tissue (10). Therefore, from a whole-body perspective, insulin has a “fat-sparing” effect by driving most cells to preferentially oxidize carbohydrates instead of fatty acids for energy. Insulin also regulates glucose homeostasis at many sites, reducing hepatic glucose production (HGP) (via decreased glucose biosynthesis [gluconeogenesis] and glycogen breakdown [glycogenolysis]) and increasing the rate of glucose uptake, primarily into skeletal muscle and adipose tissue.

A very interesting review that hypothesized on a link between diabetes and fructose said the following (Johnson et al., 2009):

For example, very high doses of fructose (250 g/d x 7 d) cause insulin resistance in 1 wk (147), whereas slightly lower doses (216 g/d for 4 wk) only induce insulin resistance at sites where fructokinase is highly expressed (liver and adipocyte) (148), and even lower doses (100 g/d x 4 wk) result in no insulin resistance at all (149).

If you read through any significant amount of human biology on diet it's impossible to avoid the fact that the hormone system (and insulin and growth hormone in particular) is paramount in determining whether the body is in a state of fat gain or fat loss. It's only at the nutritional level that the facts become obscured by experimenting with too many variables at once.

If you will permit me an aside, most all of our actual information about diet and nutrition comes not from the 'top-down' approach of observation or intervention trials but from the 'bottom-up' approach of trying to establish the mechanics of human physiology. I like to call the 'bottom-up' approach the 'physicsification' of biology. Most properly the 'bottom-up' approach in biology can be described as the combination of biophysics, biochemistry, and genetics (bio-computer science).

In physics, one establishes base laws that govern a system, known as first principles, and then one gradually expands on the complexity until theory adequately matches experiment. Technically any other science can be described in terms of physics, but often we are stymied by excessive computational requirements or too many unknown, confounding factors. However, gradually scientists are slowly unraveling the secrets of biology.

The main advantage of having first principles is that it allows you to construct hypotheses that are likely true, and then test them. There are a lot of famous and successful predictions in physics. Observational nutritional science, not so much. For example, Einstein's general relativity predicted that light would bend (or 'lens') around strong gravitational objects like black holes; it does.

Now, back to the topic as to what drives visceral fat accumulation...

One potential source for abdominal fat is fats produced in the liver itself, most commonly by the conversion of carbohydrates to fat. Typically the total contribution of liver-synthesized triglycerides (de novo lipogenesis) to the total number of triglycerides in the blood stream (i.e. VLDL) is relatively small, on the order of 10 % (Marques-Lopes et al., 2001). This is too small a proportion to seriously be considered as a cause of obesity.

However, if you recall from the paragraph I quoted above, the liver only really starts to kick out a lot of lipids when you exceed its capacity for storing glycogen. A study by McDevitt et al. (2001, free access) specifically looked into the case of overfeeding versus not and what effect it had on fat synthesis in the liver. They found that with overfeeding by 50 % over basal metabolic rates, de novo lipogenesis increased 2-3 fold. Overfeeding on sugar (glucose-fructose) was uniformly worse than overfeeding on glucose, but only slightly.

A study of rats fed a diet of 60 % fructose versus conventional rat chow (Ackerman et al., 2005). After five weeks, the fructose-fed rats had 15 % higher blood pressure, 198 % higher blood triglycerides, and 90 % higher blood cholesterol levels. A similar study in overweight women found similar results: when fed 25 % of calories in the form of fructose for ten weeks resulted in a 140 % increase in circulating triglyceride levels (Stanhope and Havel, 2008). These rates of sugar consumption are consistent with soda pop intake for a significant hunk of the American populace.

One question is, why does fructose (and alcohol) intake result in visceral fat, and not the more benign sub-cutaneous or intra-muscular fat? I have one possible explanation that I like to term the 'circulatory fat deposition model.' When you ingest a toxin like fructose or alcohol, the body automatically increases circulation to the vital organs (and in particular the liver) so that it can be filtered out of the blood stream. Since any ingested substance will naturally diffuse to even concentration throughout the blood, this is the only way to preferentially increase the flux of toxin to the liver.

Fructose is well known to contribute greatly to post-meal triglyceride levels (Chong et al., 2007). The liver takes fructose and produces palmatic acid (i.e. a stable saturated fat) from it. It then releases that fat into the blood stream. Since the filtering of fructose isn't instant, the circulation in the body core is still heightened. As a result, the visceral fat tissues see a higher rate of triglyceride flux than the more benign skin or muscle fat (Note: flux in a scientific sense typically means mass or volume per second — put those Star Trek thoughts out of your mind). The visceral fat, which sees the most fabricated triglycerides floating on by, also happens to absorb the most. Hence fructose tends to promote visceral fat. On the other hand, if you ingest excess calories in the form of fat, it's not any more likely to deposit around the liver than it is your thighs, so it's not nearly so dangerous.

One sees a similar effect with amateur body-builders who ingest calorie-heavy shakes and energy drinks after or during exercise where their muscles are generating a lot of lactic acid. The body increases blood flow to those muscles to remove the lactic acid, but the fat deposits inside the muscle also see a much higher flux of fat and fat-building substrate as a result. This results in a characteristic thick and pasty muscle texture without a lot of functional power. Think of well-marbled beef steak.

If this hypothesis is true then combining dietary fat with any chemical that requires extensive liver processing (e.g. caffeine, artificial sweeteners) would also tend to result in visceral fat deposition. Oh look, a prediction. I did say something about those.

This information on de novo lipogenesis, and what we know of the fat-sparing properties of insulin, provides some support to the notion that carbohydrates and fats should not be mixed in meals. It's only when you eat an excess of glucose, or any fructose, that one can transform a pure carbohydrate meal into body fat. On the other hand, if you eat fats and carbohydrates in combination, the insulin response will prevent your body from burning the fat directly. Note that if you have a dysfunctional carbohydrate metabolism (i.e. metabolic syndrome) this precept probably does not apply. Of course this advice is only useful if you are capable of restricting your caloric intake on a pure carbohydrate diet.

Fats are satiating whereas carbohydrates most definitely are not. The hormonal reason for this is related to the fact that they each use a different mechanism for regulation. With insulin, as it ramps down, it promotes the production of ghrelin, one of the primary 'appetite' hormones. Fat metabolism doesn't appear to have a similar analogue, and as a result hunger on a high-fat diet lacks the ravenous component of the insulin roller coaster.

When you think about, there's plenty of reason to believe that carbohydrates promote over-eating. By in large, most of the plant carbohydrate sources our paleolithic ancestors would have access to all mature around the same time, late summer and fall. This is a time period when it is particularly advantageous for primitive man to pack on some fat to sustain him over the winter. On the other hand, for Joe 6-Pack with his year-round supermarket access, this doesn't work out so well.

The conclusions we can draw from this body of research are that one can safely ingest glucose regularly with the aim of not saturating the liver's glycogen storage capacity. The maximum reasonable glucose intake level will vary significantly from person to person depending on general activity level and overall health based on how insulin resistant they are. Where one gets into trouble is when you overfill your liver by eating too many calories, with a significant fraction of glucose calories, or significant fructose intake (likely in the form of sugar or corn syrup). This is likely to lead insulin resistance and liver dysfunction.